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Antidepressants in Oncology: Reason and Choice

Riccardo GV Torta, MD; Marco Miniotti, PsycholD, and Paolo Leombruni, MD

Corresponding author: Prof. Riccardo GV Torta

Department of Neuroscience, University of Turin

Clinical and Oncological Psychology Unit,

Via Cherasco 15, 10126, Turin, Italy

Telephone: 0039-011-6636327

Fax: 0039-011-6963487

Email: riccardo.torta@unito.it

Acknowledgments

None.

Funding

No funding was received for this article.

Declaration of interest

The authors report no declarations of interest.

Other disclosures

None.

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Summary

The medications known as antidepressants are the group of psychotropic drugs used most often in

psycho-oncology for their wide spectrum of action, ranging from mood improvement to the control

of anxiety and pain. Antidepressants are drugs that act on the whole body rather than just the central

nervous system. They also modulate the hormonal and immune systems, particularly normalizing

stress-induced alterations. In oncology, the choice of an antidepressant must involve consideration

of the symptoms and the dimensional aspects more than strict diagnostic criteria. A careful

evaluation of the balance between effectiveness and safety, considering the possibility of

interactions between antidepressants and oncological treatments, is crucial. In that context, this

paper discusses each class of antidepressant relative to the present research literature concerning the

specific use of each drug in oncological patients, noting that criteria of effectiveness and safety can

differ from those established for the general psychiatric population without organic comorbidity.

Finally, some aspects of the use of antidepressants in the treatment of patients with pain will be

discussed, as these drugs exert an intrinsic antalgic activity even when depressed mood is not

present. Indeed, antidepressants act not only on the somatic modulation of pain, but they are also

effective on the emotional and cognitive aspects of pain, therefore intensifying the analgesic activity

of traditional painkillers.

Key words

Antidepressants, Oncology, Pain.

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Introduction

Despite evidence that the treatment of depression induces a significant improvement of the patient’s

quality of life and reduces mortality from cancer, pharmacological treatment is used in less than 5%

of depressed oncological patients (1-4). Furthermore, the use of antidepressants is no longer limited

to the treatment of mood disorders but has been expanded to include treatment of anxiety disorders,

pain and the somatic consequences of chronic stress (5).

Within psycho-oncology, it is important to reduce the use of several classes of drugs, such as

benzodiazepines and neuroleptics, that mainly exert a symptomatic and tactical activity that is

useful in critical situations and short term interventions, but their use is inadvisable as long term

treatments because of their propensity to increase fatigue. More appropriate is the use of

antidepressants (and sometime atypical antipsychotics) that exert a curative activity and, for newer-

generation antidepressants, have a high safety in long-term treatments (6).

In fact, the first criteria that must be met when choosing a psychopharmacological compound in

psycho-oncology relate to safety and tolerability, noting that these criteria can change among the

different oncotypes. An antidepressant must primarily manage specific clusters of symptoms that

are more frequent in depressed oncological patients, including pain, fatigue, hyporexia and weight

loss; these symptoms are no less important than nuclear depressive symptoms such as anhedonia

and mood deflection.

The next step in choosing a compound will be the evaluation of pharmaco-dynamic and kinetic

characteristics of antidepressants, particularly when used concomitantly with oncological drugs. For

example, the use of paroxetine with taxanes is to be avoided, and caution must be used to prevent

specific side effects that can be devastating in some patients, such as the anticholinergic activity of

tricyclic antidepressants (TCA) in patients with reduced gastrointestinal motility, the additive effect

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of serotonergic antidepressant-related nausea with similar chemotherapeutic side effects, or an

antihistaminergic sedation in asthenic patients (7-9)

Iatrogenic factors inducing depression

Several drugs used in general medicine and sometimes in oncological patients, such as beta-

blockers, anti-hypertensive drugs, and barbiturates, can induce depression. In addition, the

widespread use (for nausea or sedation) of high-potency neuroleptics, such as haloperidol, can

cause dopaminergic depletion with consequent depression. Alternatively, corticosteroids can induce

both depression and elation, depending on the individual’s response.

Special attention must be paid to the use of interferon because of the possibility of its inducing a

worsening of mood, related to the increase of pro-inflammatory cytokines (10-13).

Also of note, an iatrogenic estrogenic depletion (surgically or pharmacologically induced) can cause

a severe depression and an increase of the hot flushes phenomenon. For the latter, an estrogenic

implementation is obviously inconvenient, and several antidepressants have demonstrated good

effectiveness, with a normalization of thermoregulation due to estrogenic production within the

central nervous system induced by antidepressants (14-15).

It is very important to be aware that the neurotoxicity caused by several chemotherapeutic agents

(e.g., taxans, vinca alkaloids, or heavy metals) can induce not only peripheral neuropathies but also

cognitive and emotional problems, such as depressed mood, memory impairment, and irritability

(16-20).

Reasons for an antidepressant intervention in oncological patients

Depression in oncological patients causes a worsening of quality of life, a higher risk for the

emotional and somatic consequences of chronic stress, physical, social and occupational functional

impairment, a reduced adherence to diagnostic procedures and treatments as well as a dramatic

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increase in suicide risk. In spite of the high prevalence of depression in oncological patients (with

wide variability depending on the disease phase and treatment), only a small percentage of

depressed oncological patients take advantage of antidepressant treatment (4, 21-24). The poor

management of depression increases pain perception and reduces the patient’s tolerance for the side

effects of oncological therapies.

It is mandatory to make a correct diagnosis of any form of depressed mood in a patient with cancer.

Recommendations include using self-evaluation instruments and then studying in depth, with a

semistructured clinical interview, those patients that demonstrate scores higher than a screening cut-

off (25).

A serious clinical mistake is to consider depression in oncological patients as an unavoidable

pathology and consequently not responsive to drugs. The correct antidepressant treatment can

improve depression in oncological patients similarly to functional depressed patients (26).

However, an antidepressant’s effectiveness in oncology must be evaluated not based on a simple

rating scale score reduction but, above all, based on functional recovery, improvement in the quality

of life and the change toward more adaptive coping styles.

The pathogenesis of emotional disorders in oncology is strictly related to the biopsychosocial

model, with differing importance among individuals and disease phases of the biological,

emotional-cognitive and social components. Consequently, the most efficacious therapeutic

interventions will be an integration of a pharmacological intervention to correct the biologic

alterations (e.g., transmitter-related, hormonal, immunological, and neurotrophic) and/or a tailored

psychotherapy to modify the patient’s cognitive and emotional defense strategies and/or supporting

the patient when the social context problematically affects emotional parameters.

In this context, antidepressants are the most efficacious class of medication because of their activity

on mood, anxiety, stress, and pain (27,28).

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Guideline for the use of antidepressants in oncological patients

When the diagnosis of depression is made, antidepressants must be used as the pharmacological

first line of treatment. In fact, the use of benzodiazepines when depressive symptoms are present is

still frequent. Oncologists should have a basic knowledge of antidepressants to prescribe as a first

step for patients that refuse a psychiatric consultation, thus avoiding the consequences of lack of

treatment and maintaining direct management of the patient. The most favorable conditions are the

presence of a medical psycho-oncologist on the oncological team or the presence of a dedicated

psychiatrist, expert in the use of antidepressants in oncological patients.

In oncology, the greatest risk of non-adherence is present in the first weeks of an antidepressant

treatment, when side effects outweigh the therapeutic response. This is because the latency of

antidepressant activity on anxiety and mood is about three to four weeks. During this latency

period, it is essential to provide the patient with adequate information, psychosocial support (from

the therapeutic staff and family) and, when necessary, pharmacological management of the

antidepressant’s side effects (such as activation, nausea, or dizziness).

In almost all patients with severe depression, suicidal ideation can be present. An increased risk of

suicide is likely in those patients in which a psychomotor disinhibition, induced by an

antidepressant, takes place before a nuclear improvement of depression is reached. In this situation,

for an outpatient, monitoring of the patient by the family is mandatory, and it is important to have

an open and reassuring discussion with the patient concerning his or her suicidal ideation. In all

patients with chronic severe uncontrolled pain and depression, the suicide risk is significantly

increased (29).

Antidepressants behind depression

Depression as a consequence of a reduction of neurotransmitters is the major hypothesis used to

explain several clusters of symptoms that can be specifically linked to a serotonergic, dopaminergic

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or noradrenergic deficits. Likewise, the current classification of antidepressants is based on this

neurotransmitter-related hypothesis: selective serotonergic reuptake inhibitors (SSRIs), selective

noradrenergic reuptake inhibitors (NARIs), and serotonergic and noradrenergic reuptake inhibitors

(SNRIs).

If depression is actually a systemic disease, seen not only the neuropsychiatric context but also as a

disease that involves the total body, other pathogenetic hypotheses complementary to the

neurotransmitter-related hypothesis must be considered.

Moreover, the neurotransmitter-related hypothesis of depression must be considered as a systemic

pathology because 5HT, NE and DA are systemic transmitters and not only transmitters within the

brain. In contrast, depression can also be related to hormonal, immunological, and trophic

alterations. In the hormonal hypothesis of depression, several circuits are involved: the

hypothalamus-pituitary-adrenocortical axis (HPA), the hypothalamus-pituitary-gonadic axis (HPG)

and the hypothalamus-pituitary-thyroid axis (HPA).

An important relationship exists between estrogen levels and mood, as confirmed by depression

during menopause or after delivery; as previously mentioned with respect to the problem of hot

flushes, antidepressants are able to increase the estrogen level produced within brain, thereby

regulating the emotional responses related to these hormones.

Concerning the HPA axis, it is well known that stress circuits are involved in the modulation of

anxiety and mood symptoms (30). The first step in the activation of the HPA axis, that is, the

release of the hypothalamic factor CRF (Cortisol Releasing Factor), is in itself able to immediately

activate the same behavior and autonomic responses that are reinforced by the activation of HPA

circuits in toto, that is, ACTH, cortisol, vasopressine and so on. Within these circuits,

antidepressants reduce the excessive CRF response and the downstream cortisolemic and autonomic

alterations.

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The chronic release of glucocorticoids during a prolonged HPA activation can induce hippocampal

neuronal death and, consequently, a shrinkage of this area, as found in several neuroimaging studies

of pathologies characterized by chronic stress (i.e., depression, schizophrenia, bipolar disorder, and

post-traumatic stress disorder) (31).

With regard to the neurotrophic hypothesis of depression, antidepressants exert a protective activity

on hippocampal neurons through an increase of the antidepressant-induced production of

neurotrophic factors, such as BDNF and NGF (32-34). In oncology, such neurogenic effects

facilitated by antidepressants can be useful to counteract the neuronal damage induced by some

chemotherapies, thus reducing the neuropathic, cognitive, emotional and biological consequences

during chemotherapies (36, 37).

Of major importance for the use of antidepressants in oncology is the immunological hypothesis of

depression, that is, that chronic stress can induce a “neuroinflammation” through an increased

release of pro-inflammatory cytokines. Particularly at the Central Nervous System (CNS) level, the

activation of microglia causes several responses, including on the one hand, an increase of pro-

inflammatory cytokines, a reduction of glutamate reuptake and an increase of glutamate release

(increasing excitoxicity) and on the other hand, an induction of IDO, an enzyme that can divert

tryptophan from the pathway of serotonin production (causing depression) to the pathway of

kinurenines (more details in 38).

An example of the clinical consequences of cytokine increase is a cluster of symptoms (such as

apathy, hyporexia, increased sleep, libido reduction, and hyperpathy) that are similar during

inflammatory diseases (the so-called sickness behavior) and depression. This cluster may be due to

the same background in both pathologies, that is, it may be linked to cytokine activation.

The role of antidepressants in this pathogenetic key is well demonstrated in that they induce an

increase of anti-inflammatory cytokines that counteracts the depressing activity of pro-

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inflammatory ones. This statement is largely confirmed by the protective activity exerted by

antidepressants against depression induced by interferon (10, 11).

The choice of an antidepressant in oncology

The choice of an antidepressant in oncology must correlate more strictly with the dimensional

characteristics of depression, such as the particular symptomatological clusters of each patient, than

to rigid categorical criteria as defined by the nosographic manuals (such as DSM or ICD) because

these latter criteria are not suitable in cases of comorbidity.

In the choice of a drug, we have first to consider the following: 1) the clinical-symptomatological

dimensions that are related to different kinds of cancer (for example, gut motility in colon cancer,

the prolactin pharmacological growth in hormone-dependent breast cancer, or the presence of

uncontrolled pain); 2) the phase of the cancer disease (an unwanted side effect, for example,

sedation, can become useful in another situation in the same patient); 3) the risk of additive effects

of antidepressant side effects and concomitant chemotherapeutic side effects (for example,

mucositis from chemotherapy and dry mouth from TCAs, nausea from chemotherapy or nausea

from serotonergic antidepressants); 4) the need to change psychopharmacological intervention

based on changing symptoms (for example, anxiety, insomnia, fatigue, or pain).

Another step in making the choice of an antidepressant is to consider the pharmaco-dynamic and

kinetics characteristics, particularly concerning the possible interaction with oncological drugs

during polypharmacotherapeutic interventions. For example, when a women is taking tamoxifen,

the serotonergic antidepressant paroxetine must be avoided (see section “interactions”), or the risk

of a serotonergic syndrome is increased when tramadol (analgesic) and venlafaxine (antidepressant)

are prescribed together (39,40).

Antidepressants classes in oncology: the pros and cons

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The wide range of choice among different classes of antidepressants and among antidepressants

within each class allows for treatments tailored to each patient, with particular regard to the balance

between effectiveness and safety of such a therapeutic regimen.

Some antidepressants are not usually used in psycho-oncology for problems of safety, for example,

the Monoamino-Oxidase Inhibitors (MAO-I), and such classes will not be treated in this article.

Tricyclics (TCAs), which are first-generation antidepressants, have a broad spectrum of action (on

5HT and NE) and also a strong activity of blockade on several receptors (i.e., adrenergic,

histaminergic, and muscarinic). With this profile, TCAs demonstrate a high presence of autonomic

side effects (i.e., dry mouth, constipation, and orthostatic hypotension) that are very restricting in

oncological patients; the effectiveness is good (40-50% of oncological patients with depression

respond), but the tolerability is low (17-32% of treated patients drop out) (21).

Moreover, TCAs are cardiotoxic, with a delayed conduction, a QTc prolongation and possible

rhythm alterations, with particularly high risk in oncological patients with a cardiomyopathy

secondary to chemotherapy or radiotherapy (41, 42).

Amitriptyline is useful in neuropathic pain, but in this context, the high incidence of dose-related

side effects requires low dosages (mainly less than 50 mg), which are enough for antalgic activity

but are inadequate for mood treatment and, consequently, are unable to restore the pain threshold

lowered by depression (43).

Trazodone is a non-tricyclic antidepressant used fairly often in psycho-oncology, which

demonstrates at low doses an inhibition of the 5HT reuptake, but at high doses is a 5HT agonist;

this activity due probably to its main metabolite. Trazodone exerts a sedative activity through its

alfa-1 and H1 blockade and is frequently used at a dose approximately 50-75 mg in the evening as

alternative to BDZs when these compounds are inappropriate. The dosage useful for antidepressant

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activity is approximately 150-300 mg/day (44). Its efficacy on insomnia and delirium suggests the

possible use of trazodone also in palliative care (45).

Reboxetine is a norepinephrine reuptake inhibitor (NARI) that demonstrates an activating and

socializing activity without significant metabolic interactions. The main problem in oncological

patients is the frequent and sometime severe urinary hesitancy in men with present or potential

urinary troubles. The use of reboxetine in oncology is supported by an open study demonstrating

tolerability and good efficacy on depression in patients with breast cancer (46). An interesting area

of application for the noradrenergic reboxetine could be the treatment of fatigue or sexual

disturbances induced by SSRIs, but controlled studies are needed.

Selective Serotonin Reuptake Inhibitors (SSRIs) are a class of compounds (including fluoxetine,

fluovaxamine, paroxetine, sertraline, citalopram and escitalopram) that present a unique mechanism

of action (the selective inhibition of the 5HT reuptake, blocking the 5HT presynaptic transporter)

but with a differentiated clinical profile due to minor pharmacodynamic activities. For example,

paroxetine is the only SSRI with minimal anticholinergic activity, and citalopram shows a modest

antihistaminergic blockade.

SSRIs differ among themselves concerning metabolism and kinetics. Paroxetine and fluoxetine are

potent inhibitors of the isoenzyme 2D6 of cytochrome P450 and can increase the catabolism of

other compounds that are metabolized through the same isoenzyme, for example, tamoxifen.

The half-life of all SSRIs is between 7 and 33 hours, while fluoxetine (with its main metabolite

norfluoxetine) has a half-life of 7-10 days. All compounds can be used once a day, except

fluvoxamine, which must be given twice a day.

In spite of their good global tolerability in oncological patients, the increase of serotonergic tone

due to SSRIs suggests some cautions, particularly in the first one to two weeks of treatment. Nausea

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is the most frequent side effect of SSRIs, occurring in about 20-25% of patients in the first days of

the treatment and disappearing within a few days. This side effect, although subjective and

temporary, can contribute to a patient's non-adherence, particularly if given at close range with

chemotherapies. SSRI treatments have to start 10-15 days before chemotherapy to avoid the overlap

of such side effects. Moreover, if nausea becomes an operational problem with a risk of drop-out, it

is useful in association with a substituted benzamide (levosulpiride or amisulpride). Amisulpride,

besides attenuating the nausea, induces a faster antidepressant response (48, 49). Less frequent are

constipation (13%) and dry mouth (18%), particularly with paroxetine, hyperhidrosis (10-15%) and

tremor (approximately 10%). Tremor can be an important and early sign for a serotonergic

syndrome when the SSRI is associated with other compounds, for example, tramadol, which exerts

an adjunctive serotonergic activity.

Different side effects are observed among SSRIs: sertraline mainly exerts an increase of guts

peristalsis, and paroxetine mainly induces constipation; in the first phases of treatment, fluoxetine

and escitalopram present a possible activation that requires a transient BDZ, even if, after a few

weeks, all SSRIs demonstrate similar anti-anxiety activity (27). In oncological patients, particularly

in the presence of hematological alterations in platelets, SSRI use must be monitored because of

their anti-aggregation activity, especially if the patients are taking antiplatelet drugs. However, the

bleeding risk during SSRI treatment alone is not increased in comparison with the general

population (50,51).

Patients that have a reduction of dopaminergic functionality, such as exhausted individuals and

those treated with SSRIs, can incur extrapyramidal symptoms, particularly tremor and bradykinesia.

This is because an SSRI-related increase in 5HT can reduce the dopamine levels at basal ganglia

(52). The same mechanism, i.e., the serotonergic inhibition of dopamine, occurs also at the cortico-

frontal level and is responsible for the emotional blunting sometimes observed in patients treated

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with SSRIs. This effect can be counteracted by drugs with noradrenergic or dopaminergic activity,

such as venlafaxine, duloxetine or bupropion.

The number of clinical trials of SSRIs in oncology is higher than with all other classes of

antidepressants, but it is still inadequate given the clinical relevance of the problem (for a larger

review, see references 6 and 27).

Briefly, from these studies, it appears that paroxetine demonstrates a similar effectiveness to

amitriptyline but a better tolerability (53); paroxetine is more effective than placebo in preventing

depression in patients with melanoma who are being treated with interferon (54); paroxetine results

in a significant reduction of depressive symptoms versus placebo in patients treated with paroxetine

during chemotherapy, but without improvement of fatigue (55); fluoxetine is more effective than

placebo in oncological patients with major depression, but has more side effects (observed in 33%

of patients) (56), particularly on the gastroenteric system (57), while fluoxetine is better tolerated

than TCAs (58).

Another very important and diffuse use of SSRIs in oncology is the treatment of hot flushes induced

by ovariectomy, chemotherapies, or, more frequently, anti-estrogen approaches (such as tamoxifen

and/or aromathase inhibitors)(59,60). For such patients, the use of substitute estrogens is not

possible (because of the oncological risk), but a reduction in the intensity and frequency of hot

flushes was observed with several antidepressants, such as citalopram (61), sertraline (62),

paroxetine (63-65) duloxetine and escitalopram (66). This anti-hot flush activity is probably due to

the intra-cerebral estrogenic increase induced by antidepressants and a consequent reduction of

thermo-dysregulation. Caution must be used with paroxetine in association with tamoxifen because

of the presence of pharmaco-kinetic interactions reducing, in part, the clinical activity of tamoxifen

(see section: "Pharmacologic interactions of antidepressants in oncology").

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The SNRIs (Serotonin Norepinephrine Reuptake Inhibitors) are the antidepressants venlafaxine,

duloxetine and milnacipram, named “dual” because they act on both norepinephrine and serotonin

reuptake inhibition. Another “dual” is buproprion that inhibits the reuptake of norepinephrine and

dopamine (NDRI). Mirtazapine also demonstrates an activity on NE and 5HT but with a different

mechanism (through an activity on pre-synaptic NE receptors and on selective post-synaptic 5HT

receptors) and is called NASSA (Noradrenergic and Selective Serotonergic Antidepressant).

SNRIs demonstrate the same broad spectrum of TCAs on NE and 5HT, without receptor H1, alfa1

and muscarinic blockade activity, thus showing a tolerability profile similar to SSRIs and safer than

TCAs. Pharmaco-dynamic and kinetic differences exist among SNRIs: venlafaxine at low doses

(75-150 mg) shows a serotonergic more than noradrenergic activity, while it is more active on both

transmitters at higher doses (150-300 mg); duloxetine is more balanced on 5HT and NE at any dose

(67,68); milnacipram is more noradrenergic than serotonergic.

The most common side effects of SNRIs are nausea, headache, restlessness, dry mouth, insomnia or

drowsiness, constipation and dizziness; all these side effects are related to the increase of 5HT

and/or NE tone, they are present in the first weeks of treatment and they then demonstrate an

attenuation or disappearance.

The noradrenergic activity results in higher efficacy on residual and somatic symptoms of

depression, particularly the painful physical symptom cluster (69). NE reuptake inhibition can also

increase the risk of hypertension (70), particularly with high doses of venlafaxine (5% of patients at

150 mg/day and 12% with doses approximately 300 mg/day); this problem is more probable in

patients with unstable hypertension; because of this, during the first period of SNRIs treatment,

pressure monitoring is recommended.

As previously described for SSRIs, SNRIs are also effective and safe in the prevention and

treatment of hot flashes, even at low doses (venlafaxine 75 mg/day; duloxetine 60 mg/day) (14,62).

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The clinical response, measured as frequency and intensity of attacks, is already present at four

weeks and improves at eight weeks (15,66). Similar data are observed for venlafaxine in terms of

autonomic phenomena observed in patients treated with hormonal therapy in prostate cancer

(71,72).

The low activity of SNRIs on the P450 system, even in the absence of controlled and targeted

studies, allows one to theorize a pharmacokinetic safety of this class as well when used during

oncological therapies (47).

An important aspect concerning antidepressant use in oncology is their neurotrophic activity,

through an antidepressant-induced increase of neuronal growth factors (such as BDNF and NGF).

This potential can be useful in reducing peripheral and central neuronal damages induced by several

chemotherapies (such as vinca alkaloids, platinum compounds and taxans). Some pivotal data

support such a hypothesis (20), both for venlafaxine, which seems to antagonize, in part, the

chemotherapeutic-induced neurotoxicity (73-76), and for duloxetine, which increases BDNF in

depressed oncological patients (35).

In oncological patients, the possibility of successfully treating fatigue with bupropion is very

interesting (76).

The relevant antalgic effectiveness of dual-acting antidepressants will be discussed later (see

“antidepressants and pain”).

The NASSA mirtazapine acts through the presynaptic alpha-adrenergic inhibitor receptor blockade,

thereby increasing the NE and 5HT release. On the post-synaptic 5HT receptors, mirtazapine shows

a selective activity, with a stimulation of 5HT1a receptors (anxiolytic and antidepressant activities)

and a blockade both of 5HT2a receptors (with reduced sexual side effects) and 5HT2c (with

potentiation of sedative side effects). Moreover, the blockade of 5HT3, which differentiates

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mirtazapine from all other serotonergic agents (which are agonists of 5HT3), is linked to an anti-

nausea effect, and as a result, mirtazapine is useful when depression and nausea are present during

chemotherapeutic treatment (77-79). The relevant anti-histaminergic activity of mirtazapine is

favorable in patients requiring sedation (for anxiety or insomnia) or when a loss of appetite

complicates the general medical situation. Nevertheless, it is appropriate to remember that the

sedative effect of mirtazapine is mainly present at 15 mg because at higher dosages (30-45 mg), the

activating noradrenergic effect (dose-dependent) counteracts the sedative one induced by the

blockade of H1 and 5HT2c (80-83).

As with SSRIs and SNRIs, mirtazapine is also useful in the management of hot flushes (84).

Substituted benzamides act as antipsychotics at high dosage (acting as D2 post-synaptic agents),

while at low doses, they demonstrate good effectiveness on somatic and depressive symptoms,

improving coenesthesis, fatigue and volition through targeted activity on mesolimbic circuits,

particularly on D3 and D4 receptors (49,85).

To this class belong compounds that demonstrate a broad clinical spectrum of action: from anti-

emetic activity (metoclopramide, cisapride and levosulpiride) to gastroprotective activity (sulpiride,

levosulpiride) and from neuroleptic activity (sultopride, tiapride) to antidepressant activity

(amisulpride, levosulpiride).

In particular, amisulpride at low doses (equal to or less than 50 mg/day) acts specifically to

antagonize the presynaptic receptors, thereby increasing dopaminergic release, particularly at the

mesocorticolimbic level. The regulation of mood and coenesthesia of this circuit is also useful in

oncological patients; for this reason, substituted benzamides have recently been put into therapeutic

protocols for quality of life improvement in oncology (49,85).

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The clinical response to amisulpride is fast, with an improvement of several depressive symptoms,

particularly the cluster related to the somatic component (i.e., asthenia, hyporexia, and avolition);

this improvement is reached within a few days (48) in oncological patients (49).

Levosulpiride is more specific on somatoform symptoms and is dispensed also for parenteral use;

very frequently, this compound is used for nausea, including in patients that demonstrate such a

symptom in the first phases of SSRI treatment (7).

For all benzamides, but particularly for the more potent ones with respect to the dopaminergic

system, such as amisulpride and levosulpiride, several clinical cautions are needed.

First, they cause a fast and relevant increase of prolactin, sometimes with galactorrhoea, oligo- or

amenorrhoea (86), and symptoms of reduced libido and erectile dysfunction. In oncological patients

with breast pathologies, benzamides are contraindicated in the phases in which tumor growth can be

significantly influenced by sexual hormones.

Benzamides can cause an increase in body weight, but this fact can be extremely useful in some

oncological patients, particularly in advanced phases of the disease.

In older patients, strict caution must be used in the temporary use of substituted benzamides, as the

presynaptic selectivity is no longer present (because of age-related dysfunction of the dopaminergic

pathways) and because benzamides can also act at low doses as a neuroleptic, blocking D2

postsynaptic receptors and inducing extrapyramidal symptoms (e.g., tremor, bradykinesia, and

rigidity) (69).

The S-adenosyl-L-methionine (SAMe) is an endogenous compound that is effective on mood and

fatigue (87-92), even if some data are conflicting (93). The SAMe is an important donor of methyl

groups, essential for the biosynthesis of several neurotransmitters (5HT,NE,DA) (94,95). After

intravenous and intramuscular administration, absorption is practically complete, while oral

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administration demonstrates a very low bioavailability. Parenteral administration shows

effectiveness that is faster than but comparable to TCAs (96).

In psycho-oncology, SAMe is indicated in the short term treatment of depression, with a fast

restoration of well-being through an improvement of asthenia or fatigue (97). At 800-1600 mg/day,

administered in 100 cc of physiological solution for 10-14 days, it is used in psycho-oncology

particularly as an enhancer during the latency of traditional antidepressant therapy or when a fast

clinical response is needed (98).

Side effects are clinically negligible. Rarely, it presents a transient activation that in bipolar patients

treated during a depressed phase can induce a fast switch.

Pharmacological interactions of antidepressants in oncology

Several drugs also used in oncology are metabolized by the cytochrome P450. Particularly with

respect to the 2D6 isoenzyme, fluoxetine and paroxetine exert a strong inhibitory activity, with a

consequent increase of plasma levels of drugs using the same metabolic pathway. The other SSRIs

and SNRIs do not demonstrate a clinically significant interaction with 2D6 (99).

Caution must be used due to the possibility of a serotonergic syndrome as a consequence of additive

effects of serotonergic compounds, for example, secondary to the concomitant use of SSRIs/SNRIs

(particularly venlafaxine) or SSRIs and tramadol (39,40,100,101). The main symptoms are

autonomic dysfunctions (e.g., fever, nausea, vomiting, diarrhea, and hyperhidrosis) and

neuromuscular signs (e.g., myoclonus, hyperreflexia, tremor, and lack of motor coordination)(102).

The clinical relevance of the interaction between paroxetine and tamoxifen is still debated,

specifically, whether there is a real clinical impact of the reduced efficacy of tamoxifen caused by

paroxetine (103,104) rather than a simple pharmakinetic interference without clinical consequences

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(105). In any case, patients treated with tamoxifen or aromatase inhibitors and that need

antidepressant treatment must be given compounds with minor activity on cytochromes (see above).

Antidepressants and pain treatment

In advanced oncological disease, more than 90% of patients demonstrate pain with different levels

of intensity (106). oncological pain shows a complex pathogenesis that cannot always be controlled

with just an analgesic approach, but rather, it frequently needs analysis and treatment of the

emotional and cognitive components, if present.

Antidepressants (AD) and anticonvulsants (AED) demonstrate a direct antalgic mechanism on pain,

independently from the presence of anxiety and/or depression and are considered as adjuvant

analgesics in each step of the WHO analgesic scale (107). Their activity is actually complete when

the emotional and cognitive components of pain are also controlled (43).

The effective therapy of chronic pain is usually the result of a difficult balance among symptom

control, the side effects of treatment and the resulting quality of life. A correct therapeutic strategy

for pain other than the mainstay physical components of pain (i.e., site, intensity, duration, and

aggravating factors) must include consideration of the suffering based on the patient’s previous

experience, beliefs about pain, personality, relational context and, particularly, on the his or her

emotional state because stress, anxiety and depression reduce the pain threshold (108). Major

depression is present in between 30 and 54% percent of patients with chronic pain (109), and the

presence of painful symptoms is highly predictive of a subsequent major depression (110).

Moreover, depression and pain share, in part, several biologic neurotransmitter-related, hormonal,

immune and neurotrophic substrates.

A norepinephrine and serotonin deficit on the one hand is considered to be a main pathogenetic

cause of depression, whereas on the other hand, the same deficit reduces the efficacy of the inhibitor

descendent system that projects from the periacqueductal griseum (PAG) to the spinal cord. An

20

increase of proinflammatory cytokines is present both in depression and in pain, as is well

supported by the flogistic sickness syndrome in which occurs a similar cluster of symptoms (i.e.,

hypovolition, asthenia, and hyperalgesia) to that observed in depression (43). During chronic stress,

which is very frequent in patients with chronic pain, the hyperactivation of the HPA axis leads to an

increased release of cortisol and consequently of cytokines, both of which are involved in pain and

depression (30).

On the neurotransmitter level, pain is modulated and transmitted through serotonergic,

noradrenergic, GABAergic, glutamatergic and opioid systems, all related to the antidepressant and

anticonvulsant mechanism of action. For example, with dual-acting antidepressants such as

duloxetine, venlafaxine, and milnacipram, the contextual increase of 5HT and NE at mesencephalic

and limbic levels (amygdala and accumbens) induces the release of endogenous opioids, with a

consequent antalgic effect characterized by a pain threshold increase and reduced pain perception

(111).

In neuropathic pain, both antidepressants and anticonvulsants act through the reinforcement of

inhibitory descendent mechanisms and the downregulation of the hyperfunctioning sodium and

calcium channels, modulating the abnormal interactions between the central nervous and autonomic

systems (112). In this way, characteristic phenomena of neuropathic pain (such as hyperalgesia,

allodynia and wind-up) are reduced by ADs and AEDs that represent the first-choice classes for this

pathology (113).

Antidepressants work on pain via a direct mechanism (114), thereby demonstrating analgesic

activity that is independent from their activity on mood. The antalgic response is faster than the

antidepressant effects; a few hours after the first administration, the reuptake inhibition exerted by

the AD increases the neurotransmitter’s intrasynaptic availability, thus acting on pain inhibitor

systems (115,116).

21

TCAs are commonly used and have been in use for a long time. In spite of their effectiveness in

reducing pain, the presence of a large number of side effects (due to their receptor blockade) limits

their use and particularly their dosage, so that the tolerable dosage is almost always inadequate for a

true antidepressant effect. From the 1980s, several antidepressant mechanisms of action on pain

were proposed: the interaction with the opioid system, the antagonism against NMDA glutamate

receptors, and, more recently, the blockade of the calcium and sodium channels and NO and

prostaglandin E2 dose-dependent inhibitions (117).

In spite of a large body of literature concerning the use of TCAs on pain, up to date studies on

neuropathic oncological pain are lacking (118). In the few studies available, TCAs are used with

low doses, utilizing their sedative and intrinsic antalgic activity without the synergic antidepressant

effect that is essential to normalize the pain threshold (43). The tertiary amines (such as

amitriptyline) are more effective than secondary amines (such as nortriptyline and desipramine)

because of their larger receptorial blockade (119).

SSRIs are also effective in several pain syndromes, both experimental and clinical, and although

their main mechanism of action is serotonergic, they are linked to the opioid systems (120,121). In

several studies on neuropathic pain, SSRIs were less effective than TCAs but better tolerated,

particularly in long-term treatments (122).

The dual antidepressants (venlafaxine and duloxetine) are implemented within the guidelines for the

use of ADs in neuropathic pain because of their favorable balance between effectiveness and safety,

as an alternative to less well-tolerated TCAs (113).

In our clinical experience, venlafaxine (75 mg/day) reduces uncontrolled pain and concomitantly

acts on its cognitive and emotional aspects, encouraging a better adjustment of the patient to the

disease (123). Duloxetine is the first antidepressant approved by the Food and Drug Administration

(FDA) for the treatment of neuropathic pain, particularly in diabetic neuropathy and, more recently,

22

for tension-related pain (124,125). Duloxetine also demonstrates a contextual activity on pain and

mood in oncological patients (26).

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